Primary (essential) hypertension affects 28 % of the adult population in the United States and leads to premature cardiovascular, cerebrovascular and renal disease. The overall goal of Project #2 is to understand the interactions among the major renal Na+ regulatory pathways (dopamine 1, [DIR], dopamine 3 [DSR], and angiotensin type 1 [ATIR] receptors) which are critical to the regulation of blood pressure in humans. In experimental animals, the renal renin-angiotensin system and the renal dopaminergic system independently, and in concert, regulate renal Na-i- excretion, and defects in these pathways can lead to hypertension. We have reported that the hypertension in mice overexpressing the human G protein-coupled receptor kinase type 4 variant, GRK4 A142V is associated with decreased renal Dl R expression and function and increased ATI R expression and function A similar mechanism may be operating in human essential hypertension. Expression of GRK4 variants in cell lines replicates the Dl R defect noted in human renal proximal tubule cells from hypertensive subjects. Inhibition of GRK4 function or expression normalizes DIR function in human renal proximal tubule cells/cell lines expressing GRK4 variants. Moreover, renal selective prevention of the expression of GRK4 in spontaneously hypertensive rats attenuates the development of hypertension. The uncoupling of Dl R in hypertension impairs the inhibitory paracrine regulation by dopamine (DA) of renal Na+ transport in the proximal tubule and even more distal nephron segments. Because DA, via DiRs and D3Rs, normally antagonizes the increase in Na+ reabsorption caused by angiotensin II, via ATlRs, enhanced renal Na-i- reabsorption In hypertension may be due to an unopposed ATI R action (by DA). The overall hypothesis of Project #2 is that ATI R-mediated antinatriuresis is opposed by D1Rs and D3Rs, acting in concert in normal human subjects, and that this protective mechanism is deficient in patients with essential hypertension. Three specific aims will determine the interactions among DiRs and D3Rs and ATlRs and their consequences in terms of Na+ excretion: (1) to test the hypothesis that D3R activation induces natriuresis, in part, (continued on next page)